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Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells

  • Kibem Kim1,
  • Andrew Skora2,
  • Zhaobo Li2,
  • Ada Tam3,
  • Luis Diaz2,
  • Nickolas Papadopolous2,
  • Lee Blosser3,
  • Kenneth Kinzler2,
  • Bert Vogelstein2 and
  • Shibin Zhou2
Journal for ImmunoTherapy of Cancer20142(Suppl 3):P267

https://doi.org/10.1186/2051-1426-2-S3-P267

Published: 6 November 2014

Keywords

HDAC InhibitorPI3K InhibitorImmune CheckpointCheckpoint InhibitorEpigenetic Modulator

Recent clinical trials have shown highly promising responses in a subset of patients treated with immune checkpoint inhibitory anti-programmed cell death-1, anti-programmed cell death ligand-1 (PD-1), and anti-cytotoxic T-lymphocyte-associated antigen-4 antibodies (CTLA-4) [14]. However, immunotherapy against poorly immunogenic cancers remains a challenge. Large, modestly immunogenic CT26 tumors or poorly immunogenic metastatic 4T1 tumors in mice were unresponsive to anti-PD-1 and anti-CTLA-4 treatments. Co-treatment with DNA methyltransferase and HDAC inhibitors, and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of the tumor-bearing mice. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). In addition, reduction of MDSCs using antibodies directed against them or a PI3K inhibitor that reduced circulating MDSCs had similar antitumor effects to those observed with the epigenetic modulators. Our results show that elevated myeloid-derived suppressor cells (MDSCs) are responsible for the resistance to checkpoint inhibitors and that elimination of MDSCs can lead to cures of experimental, metastatic tumors.

Authors’ Affiliations

(1)
Medical Scientist Training Program, Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
(2)
Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA
(3)
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, USA

References

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Copyright

© Kim et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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